Reduction of subcutaneous fat layers, or adipose tissue, is an aesthetic treatment for which there is a growing demand. One method, liposuction, is a very aggressive invasive treatment requiring local or general anesthesia, and the subsequent healing process is very long and painful. Methods for non-invasive local reduction of fat are based on the delivery of electromagnetic or sound energy through the skin into the subcutaneous adipose tissue. The main challenge with non-invasive treatment of fat tissue is to transfer the energy through the outer layers of the skin, and concentrating it to the required level in the fat tissue with minimal collateral damage to the skin layers and deeper body tissues.
U.S. Pat. No. 5,143,063 describes a method for destruction of fat cells (adipocytes) in subcutaneous adipose tissue, in which radiant energy is focused into these cells. The radiant energy may be electromagnetic in the microwave range, or ultrasound. The major mechanism for cell destruction is the heat generated by the radiant energy. Only at the focal volume is the energy density high enough for cell destruction, while outside the focal volume the energy density is lower than the damage threshold. There is no specific selectivity for destruction of fat cells, only a geometrical selectivity created by the focusing.
U.S. Pat. No. 5,158,070 discloses use of ultrasound pulses of short duration that are powerful enough to tear soft tissue. Ultrasound pulses having a frequency between 3 MHz to 10 MHz and a pulse length of one μsec to one msec are focused in the soft tissue to effect tearing and destruction. Due to the application of short intense pulses, mechanical, and not thermal, effects are presumed to be responsible for the tissue destruction. The following calculation provides an estimate for the peak pressure of the ultrasound wave required for this cell tearing. Assuming a plane ultrasound wave for which the cell size is much smaller then the wavelength, the local displacement U(x) is given by:U(x)=Umax sin(ωt−kx)where Umax is the maximum displacement given by:
      U    max    =            V      max        ω  Vmax is the maximum velocity, ω=2πf, f is the frequency of the ultrasound, and k is the wave vector. For a plane wave, ω=kc, where c is the sound velocity at the tissue. Taking the derivative of U with respect to x, the strains obtained:
            ⅆ      U              ⅆ      x        =                    -        k            ⁢                        V          max                ω            ⁢              cos        ⁡                  (                                    ω              ⁢                                                          ⁢              t                        -            kx                    )                      =                            -                      V            max                          c            ⁢              cos        ⁡                  (                                    ω              ⁢                                                          ⁢              t                        -            kx                    )                    
The maximal strain is Vmax/c. The strength of a typical cell membrane has been investigated, and it was found that stretching a cell membrane by more then 2% causes it to tear, leading to cell necrosis, (Luc Fournier and Be'la Joo's, Physical review 67, 051908 (2003)). This corresponds to a strain of 0.02. Since the sound velocity in a typical soft tissue is about 1500 m/sec, for rupturing a cell membrane, Vmax has to be over 30 m/sec. For a plane wave, V=P/Z, where P is the pressure and Z is the acoustic impedance of the tissue, a typical value for Z is 1.5 MRayleigh, so that P has to be greater than 45 MPa. This number corresponds to a very intense ultrasound, which can be achieved with a very high degree of focusing, and which is obtainable at frequencies in the range of a few MHz. For example, US Patent Application No. 2005/0154431, discloses adipose tissue destruction generated by HIFU (High Intensity Focused Ultrasound), with a typical frequency of 1-4 MHz and a pressure of about 30 MPa, close to the theoretical estimate of 45 Mpa obtained above.
This method of cell rupturing is also not selective for adipose tissue cells (adipocytes) because the adipocyte membrane is not weaker than that of other cells. Also the shape and size of the cell did not enter in the above considerations. In this respect, cell destruction by rupturing the cell membrane is similar to cell destruction by heating the cells (hyperthermia). Neither method is selective for adipocytes, and any selectivity in the method relies on geometry i.e. very strong focusing of the radiation in the adipose tissue. For both methods, a high degree of focusing yields a very small focal volume where cell destruction occurs. A typical effective focal width is a few millimeters. Therefore, the focal volume has to be moved over the treated area. US Patent Applications Nos. 2005/0154431 and 2004/0106867 disclose such a system.
Another physical effect of focused ultrasound that can cause cell lysis, is cavitations. Cavitations are small bubbles, starting from initial small gas nucleation centers, which are driven larger by the negative pressure phase of the ultrasound wave. The rate of generation and growth of cavitations is an increasing function of the amplitude of the pressure, therefore an increasing function of the ultrasound power density. Under certain critical conditions, the bubbles collapse violently, generating in their vicinity shock waves and fluid jets that can destroy cells. In liquid environments, especially in aqueous solutions, there is evidence that collapse of cavitations causes cell gnecrosis and apoptosis. U.S. Pat. No. 6,607,498 discloses focusing ultrasound energy on adipose tissue to cause cavitations and lysis of adipose tissue. U.S. Pat. No. 6,113,558 discloses the application of focused pulsed ultrasound, which causes cavitations, for non-invasive treatment of tissues. This last patent contains a list of possible applications, which include the induction of apoptosis and necrosis, clot lysis, and cancer treatment. This patent includes a study on the generation of cavitations and on the optimization of pulse width and pulse repetition rate for maximizing the cavitations. The cavitation threshold for a non-degassed buffer solution and blood are in the range of 1000-1500 W/cm2, while for degassed fluids the threshold rises to 2000 W/cm2. The ultrasound frequency in these experiments was 750 kHz. Cavitation damage is not cell selective, and can be induced on many cell types. The cavitation threshold is quite high, and can be expected to be much higher inside adipose tissue, since most of the tissue volume is fat (lipid vacuoles). As with thermal treatment and mechanical rupturing of cells by ultrasound, also with cavitation, a high degree of focusing is required to ensure treatment of the selected tissue only (geometrical selectivity). There is another reason for the importance of focusing in cavitation treatment: Cavitations absorb ultrasound very strongly. Therefore, if cavitations are created close to the applicator, that is between the focal region and the ultrasound radiating transducer (for example at the skin), then most of the ultrasound energy will be dissipated there and will not reach the target tissue in the focal volume. To prevent this from occurring, the focusing must be sufficient to assure an intensity above the minimum value for cavitation at the focal volume, while the intensity at other tissues between the transducer and focal volume must be below the threshold for cavitation.
Besides ultrasound and microwave radiation, application of RF (Radio Frequency) energy can affect both the skin and subcutaneous layers. U.S. Pat. No. 6,889,090 discloses the application of RF energy for skin treatment. U.S. Pat. No. 5,871,524, describes application of radiant energy through the skin to an underlying subcutaneous layer or deeper soft tissue layers. The main energy source is RF. A bi-polar RF application, such as described in U.S. Pat. No. 6,889,090, is preferred over unipolar RF, since in unipolar RF currents flow through uncontrolled channels at the body, and may cause unwanted damage.
RF energy is applied to the body through two conducting electrodes applied to the skin between which an alternating voltage is driven. The RF current flows according to Ohm's law through the conducting tissues, generating heat, which can affect the tissue. The conductivity of the skin layers is an order of magnitude larger than that of fat tissue. Typical skin conductivity is about 0.45/m and that of adipose tissue is about 0.045/m at RF frequencies between 100 kHz and 10 MHz (S. Gabriel, R. W. Lau, and C. Gabriel, Phys. Med. Biol. 41 (1996), pp 2251-2269). Therefore most of the current flows through the skin layers, which is good for skin treatments, for example, hair removal and skin rejuvenation. However, it is less efficient for treatment of the deeper adipose layers.
U.S. Pat. No. 6,662,054 discloses the application of negative pressure (vacuum) to a region of the skin, so that this region protrudes out of the surrounding skin, and applying RF energy to the protrusion via electrodes. Under negative pressure, the path between the RF electrodes is longer along the skin than through the subcutaneous layers. Therefore, more RF energy is delivered into subcutaneous layers than through the skin. A commercial system based on U.S. Pat. No. 6,662,054 has proved efficient for treatment of cellulites (TINA S. ALSTER & ELIZABETH L. TANZI, The Journal of Cosmetic and Laser Therapy. 2005; 7: 81-85). Cellulite is clinically manifested by irregular skin contours or dimpling of the skin. It is caused by excess adipose tissue retention within fibrous septae. The skin irregularity is proportional to the subcutaneous fat projected into the upper dermis.
Most of the volume of an adipocyte is occupied by a fat fluid drop, known as a lipid vacuole. The typical diameter of the cell is 50-100 μm It tends to 100 μm in adipose tissue of obese people. Between the lipid vacuole and cell membrane, is cytoplasm. Typically the width of the cytoplasm is only a few micrometers and it is not uniform around the lipid vacuole. It can be in the range from below 1 μm in one region of the cell and 3-5 μm in other regions.
The macroscopic physical properties of adipose tissue, mass density and sound velocity, are dominated by the material of the lipid vacuole, which occupies most of the tissue volume in mature fat cells which are the cells to be treated in reduction of the fat layer. The physical properties of the lipid vacuole fluid are thus almost identical to those of fat tissue. The density of adipose tissue is about 10% lower than that of other body tissues. According to “Physical properties of tissue”, by Francis A. Duck, Academic Press Ltd., 1990, p. 138, the density of adipose tissue is 916 Kg/m3, while that of body fluids and soft tissue are above 1000 Kg/m3 (i.e. above the density of water). The dermis density is about 1100 Kg/m3, while that of muscles is 1040 Kg/m3. The cytoplasm and intercellular fluid are aqueous solutions so that their density is expected to be similar to that of other body fluids and soft tissues, i.e. in the range of 1020-1040 Kg/m3. The velocity of sound is about 1430 m/sec in adipose tissue, compared to 1530 m/sec for skin, at normal body temperature. Moreover, on page 85 of the Duck reference, the slope of the sound velocity versus temperature curve for fat is completely different from that of other body fluids. For fat, sound velocity decreases with increasing temperature, dropping to 1400 m/sec at 40° C., while that of water and other body fluids rises with temperature, and is about 1520 m/sec at 40° C. for water and higher for body fluids and soft tissues other than fat.
A basic model of the electrical properties of cells at the microscopic level can be found in Herve Isambert, Phys. Rev. Lett. 80, p 3404 (1998). The cell membrane is a poor electrical conductor and therefore behaves essentially as a local capacitor upon the application of an electric field across the cell. The charging of the cell membrane under the application of external electric field generates a stress at these membranes, yielding strain which depends on the elastic properties of the cell, and which at increased intensity can rupture the cell membrane, a phenomena known as “electroporation”.